Abstract Huntington?s disease (HD) is a genetic neurodegenerative disorder caused by an anomalous expansion of CAG repeats in the HTT gene. Psychiatric symptoms in HD, including apathy, depression, mood swings and irritability, accompany and often precede the onset of motor abnormalities, but are poorly understood and insufficiently treated. The major histopathology in HD patients is the loss of medium- sized spiny neurons (MSNs) in the striatum and pyramidal neurons in the cerebral cortex. Surprisingly, while the role of the dorsolateral striatum, a region involved in motor control, has been extensively studied in HD, the role of the nucleus accumbens (NAc), a region of the ventromedial striatum involved in the cognitive processing of reward perception, emotion regulation, and motivational salience, has been largely neglected. Thus, the first aim of this proposal will examine the progression of functional and morphological abnormalities in NAc MSNs in two mouse models of HD, the R6/2 (a model of juvenile HD) and the Q175 (a model of adult-onset HD). We hypothesize that MSNs in the NAc, particularly those expressing dopamine D2 receptors, will display early electrophysiological and morphological abnormalities. The NAc receives glutamatergic projections from the medial prefrontal cortex (mPFC), a region that plays a critical role in motivation and, when dysfunctional, can lead to psychiatric symptoms. Additionally, in pathological conditions, the mPFC-NAc synapses undergo aberrant plastic changes supported by the insertion of atypical Ca2+-permeable (CP)-AMPA receptors (AMPARs). Although CP-AMPARs mediate excitotoxicity and have been hypothesized to play a pivotal role in neurodegenerative disorders, this hypothesis has not been tested systematically in HD. Therefore, the second aim of this proposal will examine the role of CP-AMPARs at mPFC-NAc synapses in MSN dysfunction in the NAc. We hypothesize that the NAc MSNs, particularly those expressing D2 receptors, become progressively affected in HD and that reverting neuronal abnormalities occurring in the mPFC-NAc projections by disabling synaptic CP-AMPARs can restore NAc normal function and delay impending cell loss. To test these hypotheses, we will use the slice preparation to examine electrophysiological and morphological changes in D1/D2 receptor-expressing MSNs in the NAc. Furthermore, we will use optogenetic approaches to isolate and attempt to restore normal communication in the mPFC-NAc projection. Finally, the involvement of the NAc and CP- AMPARs in HD-associated psychiatric symptoms (e.g., motivation deficits) will be confirmed by behavioral measurements and neuropharmacological manipulations. Our findings will be crucial to alleviate the progression of psychiatric symptoms, thereby providing novel therapeutic tools in order to improve the quality of life of HD patients.